Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/20—Spiro-condensed systems

Definitions

• the present invention relates to new compounds having a tetrahydropyrano [3,2-d] oxazolone structure, their preparation process and the pharmaceutical compositions containing them.
• the compounds of the present invention find a very advantageous therapeutic use thanks to their angiogenesis inhibiting power.
• Angiogenesis (or neovascularization) is defined as the development and growth of new capillary blood vessels.
• the angiogenesis process is essential in many physiological situations including the development of the embryo, normal wound healing and the development of the endometrium after menstruation. Apart from these situations, angiogenesis in normal adults is very rare and the mitosis of endothelial cells which generates the walls of blood vessels is very slow, with cell renewal times measured in years.
• Abnormal angiogenesis i.e., stimulation of the growth of new blood vessels due to a pathological syndrome
• diseases including diabetic retinopathy, rheumatoid arthritis, hemangiomas and growth solid tumors.
• Angiogenesis can also play an important role in other diseases such as coronary artery disease.
• the growth of solid tumors has been shown to be entirely dependent on the constant development of new vessels
• REPLACEMENT SHEET (RULE tf) and that it is correlated, for the metastases of certain cancers, with the growing size of the primary tumor.
• angiogenesis inhibitor can therefore stop the growth of primary tumors, prevent or reduce the formation of metastases, prevent the appearance of secondary tumors.
• angiogenesis inhibitors are also useful in the treatment of the previously mentioned non-neoplastic diseases in which angiogenic activity occurs.
• the needs of therapy require the constant development of new angiogenesis inhibiting compounds in order to obtain active ingredients that are more active, more specific and less toxic.
• the present invention relates to new compounds having a tetrahydropyrano [3,2-d] oxazolone structure and having a structural and pharmacological originality compared to the compounds described in the prior art.
• Ri is chosen from the radical R and the radical -NH-CO-R,
• R is chosen from the amino radical, an alkylamino, dialkylamino, alkyl, alkenyl, aikoxy, aryl, arylalkyl, heteroaryl, heteroaryialkyl, aryloxy and heteroaryloxy radical,
• R 2 is chosen from hydrogen and an alkyl radical
• R 3 is chosen from hydrogen, an alkyl radical, the hydroxy radical, an aikoxy radical, an aryl radical, an arylalkyl radical, a - (CH 2 ) n -OR e radical, and a - (CH 2 ) radical let-NR ⁇ R 9 ,
• R4 represents hydrogen or else forms a bond with Y
• R5 is chosen from hydrogen, an alkyl radical, an aryl radical, an arylalkyl radical, a heteroaryl radical and a heteroaryialkyl radical or else forms with Y a bond,
• R ⁇ is chosen from hydrogen, an alkyl radical, an alkylepoxy radical, an arylalkyl radical, an arylalkylepoxy radical, an alkenyl radical, an alkynyl radical, an alkoxycarbonyl radical, a carboxy radical, an aryl radical and a heteroaryl radical,
• R 7 is chosen from hydrogen, an alkyl radical, an arylalkyl radical, a - (CH 2 ) n-OR ⁇ radical, a - (CH 2 ) n-0-CO-R 8 radical and a - ( CH 2 ) n-NR ⁇ R 9 ,
• R ⁇ and R 9 are chosen, independently of one another, from hydrogen, an alkyl radical, an aryl radical and an arylalkyl radical,
• n takes a value chosen from 1, 2, 3 and 4,
• X is chosen from hydrogen, the hydroxy radical, an aikoxy radical, the amino radical, an alkylamino, dialkylamino radical, the radical -O-CO-RS and the radical -NH-CO-RS, where R'1 a the same definition as Ri defined above and Y represents hydrogen,
• Y is chosen from hydrogen, the hydroxyl group and the
• R a and R b which are identical or different, are chosen, independently of one another, from an alkyl radical, an aryl radical, an arylalkyl radical, a heteroaryl radical and a heteroaryialkyl radical, or else form together with the sulfur atom which carries them an optionally substituted radical, chosen from thienyl, 1,3-dihydrobenzo [c] thien-2-yl, 2,3-dihydrobenzo [b] thien-1 -yle, perhydrobenzo [c] thien-2 - yl and perhydrothienyl,
• alkyl included in the alkyl, alkylamino, dialkylamino, arylalkyl, arylalkylepoxy, heteroaryialkyl and alkylepoxy radicals denotes a radical in which the saturated hydrocarbon chain contains from 1 to 10 carbon atoms, in straight or branched chain, and is optionally substituted ,
• alkenyl denotes a radical containing from 2 to 10 carbon atoms in a straight or branched chain, optionally substituted, and comprising an unsaturation in the form of double bond
• alkynyia denotes a radical containing from 2 to 10 carbon atoms in straight or branched chain, optionally substituted, and comprising an unsaturation in the form of triple bond
• aikoxy included in the aikoxy and alkoxycarbonyl radicals denotes a radical in which the saturated hydrocarbon chain contains from 1 to 10 carbon atoms, in straight or branched chain, and is optionally substituted
• aryl included in the aryl, arylalkyl, aryloxy, arylalkylepoxy radicals denotes an optionally substituted radical, chosen from phenyl and naphthyl,
• heteroaryl included in the heteroaryl, heteroaryloxy and heteroaryialkyl radicals denotes an optionally substituted radical chosen from furyl, thienyl, thiazolyl, imidazolyl, thiadiazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, indolyl and isoindol
• radicals thus qualified may optionally be substituted by one or more chemical entities chosen from:
• halogen chosen from fluorine, chlorine, bromine and iodine
• the present invention also extends to the process for preparing the compounds of formula (I) characterized in that the furyllithium of formula (II) is treated with the compound of formula (III):
• R 2 , R 3 , R 5 , R ⁇ and R 7 are as defined above,
• SUBSTITUTE SHEET (RULE 26) suitable, such as dichloromethane or tetrahydrofuran, at a temperature between 0 ° C and 22 ° C, is rearranged into pyranone of formula (V):
• R 2 , R 3 , R 5 , R ⁇ and R 7 are as defined above,
• R 2 , R 3 , R 5 , R ⁇ and R 7 are as defined above,
• reaction schemes (I), (II) and (III) were thus carried out:
• Reaction 1 the reduction of the ketone function to alcohol is carried out in an appropriate solvent, tetrahydrofuran for example, at low temperature, from -78 ° C to 20 ° C, the reducing agent being chosen from the hydrides usually used for this type reduction.
• a reducing agent which is particularly suitable in the present reaction is lithium triethylborohydride.
• Reaction 2 The etherification of the alcohol function is carried out according to conventional methods known to those skilled in the art.
• the alcohol, treated with a base, such as sodium hydride, is subjected to the action of an alkyl halide.
• SUBSTITUTE SHEET (RULE 26) of formula Alk-X, where Alk represents an alkyl chain as defined above and X represents a halogen atom.
• Reaction 3 The alcohol function is subjected to dehydration, according to conventional techniques, for example by heating in the presence of paratoluenesulfonic acid in benzene.
• Reaction 4 the hydrogenation reactions are carried out conventionally in the presence of catalytic quantities of palladium and hydrogen, at atmospheric pressure or under low pressure, at a temperature between 10 ° C. and 80 ° C.
• the preferred operating conditions for the catalytic hydrogenations of the present invention are those where hydrogen is at atmospheric pressure, and at room temperature, the reactions being continued until complete disappearance of the compound to be hydrogenated.
• Reaction 5 the esterification of the alcohol function is obtained by the action of a halide of formula R'-CO-X where X represents a halogen and R 'is as defined above, on the alcoholate conventionally obtained from alcohol that you want to esterify.
• Reaction 6 reaction carried out under the same operating conditions as those used for reaction 5 described above, replacing the halide R'-CO-X with the isocyanate of formula R'-CO-NCO, where R 'is as defined above.
• Reaction 7 the ketone function is here subjected to a nudeophilic attack under the conditions known to the person skilled in the art, for example attack by an afl yllithium or by an aiylalkyllithiurn, where the terms alkyl and arytalkyi are as defined above
• Reaction 8 the transformation of the ketone function into an amino function is obtained by treatment with ammonium acetate (to obtain a primary amine), with an amine of formula H 2 NAIk (to obtain a secondary amine) or with an amine of formula HNAlkAlk * (to obtain a tertiary amine), where Alk and AK each represents one alkyl chain as defined above
• the reaction is carried out in the presence of sodium cyanoborohydride, in polar protic solvent, in alcoholic solvent for example , in methanol or tethanol.
• Reaction 9 the reaction with hydroxylamine hydrochloride and sodium acetate provides the expected oxime.
• the reaction medium is an aprotic polar medium, preferably alcoholic, methanol or ethanol for example.
• the reaction temperature is chosen, depending on the solvent used, in a range from 20 ° C to 80 ° C, 40 ° C for example in methanol.
• Reaction 10 The oxime (XIX) is treated as described in reactions 5 or 6.
• This reaction is carried out in tetrahydrofuran at a temperature between 60 ° C and 70 ° C, the phosphonium ylides being obtained by the action of potassium t ⁇ rtiobutytate.
• Reaction 13a the spro-epoxy function is obtained by the action of dimethylsulfide ylide on the compound of example (VI).
• Reaction 13b the sp / ro-epoxide function is obtained by the action of metachloroperbenzoic acid in dichloromethane, at 0 ° C.
• R, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and Y are as defined above,
• the compounds of the present invention can also be prepared from a compound of formula (II 1 ):
• R 2 , R 3 , R 5 and R 7 are as defined above and R ' 6 represents an alkyl radical or an arylalkyl radical, the alkyl chain comprising from 1 to 8 carbon atoms.
• radicals -CO-NH-CO-R and -CO-NH-CO-R ', where R and R' are as defined above, when they replace the compounds of formula (I) can advantageously be selectively cleaved into radicals -CO-NH 2 .
• This cleavage reaction is preferably carried out on a silica column, by chromatography
• any geometric or optical isomers of the compounds obtained at each of the stages of the syntheses described above may be carried out at any time deemed appropriate by those skilled in the art.
• the various reactions presented above may be carried out in a different order from that presented in the present invention and deemed more suitable by those skilled in the art.
• the compounds of formula (I) have interesting pharmacological properties. Indeed, these compounds are powerful angiogenesis inhibitors which have the advantage of presenting, compared to the reference compounds, a much less general toxicity. They therefore have an excellent therapeutic index. These compounds thus find a therapeutic application as anti-tumor agents, in the inhibition of the formation and the growth of metastases, as well as in the treatment of diabetic retinopathy, rheumatoid arthritis, hemangiomas and arterio-coronary diseases, and more generally in conditions due to or related to angiogenesis disorders.
• a subject of the present invention is also pharmaceutical compositions containing the compounds of formula (I), their possible optical and / or geometric isomers or their optional addition salts with a pharmaceutically acceptable acid, alone or in combination with one or more excipients or inert and non-toxic vehicles.
• pharmaceutical compositions according to the invention particular mention will be made of those which are suitable for oral, parenteral, nasal, rectal, perlingual, transdermal, ocular or respiratory administration, and in particular simple or coated tablets, sublingual tablets, capsules, suppositories, creams, ointments, dermal gels, patches, injectable or drinkable preparations, aerosols, eye or nasal drops.
• the useful dosage varies according to the age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated treatments and ranges between 0.01 and 1 g per day, in one or more administrations.
• Step B 2- (heptyn-1-yl) -2-methyl-3-oxo-dihydro [2f yran-6-ol
• Step C 1-chloroacetyl-5- (hept-1-ynyl) -5-methyl-dihydro-pyrano [3,2-d] oxazole-2,6-dione
• SUBSTITUTE SHEET (RULE 26 ⁇ 60 mg (0.18 mmol) of the compound obtained in Example 2 are subjected to an oxidation reaction in the presence of 6 ml of a solution of acetone saturated with dimethyldioxirane at 0 ° C. The reaction medium is stirred for one hour at this temperature. The solvent is evaporated under reduced pressure and the oily residue thus obtained, azeotroped with toluene. After concentration under reduced pressure and drying under vacuum, the expected compound is obtained in the form of a lyophilisate.
• Elementary analysis (raw formula: molecular mass: 359.81)
• Step A 5- (h ⁇ pt-1-ynyl) -5-methyl-6-methylene-dihydropyrano [3,2-d] oxazol-2-one
• reaction medium After stirring for two hours at room temperature, the reaction medium is hydrolyzed with a saturated solution of sodium chloride and then extracted with ether.
• the usual treatment of the organic phase provides, after purification by chromatography on silica gel (eluent: heptane / ethyl acetate, 2: 1), 2.08 g of the expected compound.
• Eta p e B 6- [5- (hept- 1 -ynyl) -5-methy l-tetrahydropyrano [3,2-d] oxazol-2- one] -sp / n 2'-oxirane
• Step C 6- [5- (hept-1-enyl) -5-methyl-tetrahydropyrano [3,2-d] oxazol-2- one] -sp / ro-2'-oxirane
• Step D 6- [5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydropyrano- [3,2-d] oxazol-2-one] -sp / ro-2'-oxirane
• Step E 6- [1-chloroacetyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one] -sp / ⁇ > 2'- oxirane
• SUBSTITUTE SHEET (RULE 26) Compound obtained according to the procedure described in Example 4, steps A, B and E, from 5-methyl-5-heptyl-dihydropyrano [3,2-d] oxazole-2,6-dione in step A, itself obtained by catalytic hydrogenation (palladium, barium sulphate, in ethyl acetate, 1 atmosphere) of the diastereoisomer A of 5- (hept-1-ynyl) -5- methyl-dihydropyrano- [3 , 2-d] oxazole-2,6-dione obtained in Example 1. Elemental analysis: (crude formula: Ci7H 26 CIN0 5 molecular weight: 359.85)
• Step A 5- (hept-1-enyl) -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione
• the diastereoisomer A of 5- (hept-1-yn-1-yl) -5-methyl-dihydropyrano [3,2-d] - oxazole-2,6-dione, obtained in step C of the example 1, is subjected to catalytic hydrogenation according to the procedure described in Example 2.
• Step B 6- [1-chloroacetyl-5- (3-pentyloxiran-2-yl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one] -sp / ro-2'- oxirane
• Step A 5- (heptyn-1-yl) -6-hydroxy-5-methyl-tetrahydro ⁇ yrano [3,2-d] oxazol-2-one
• SUBSTITUTE SHEET (RULE 26) 15% hydrogen peroxide and then extracted with ethyl ether. After drying the organic phase over sodium sulfate and then concentrating under vacuum, 200 mg of the expected product in the form of a yellow oil are obtained.
• Step B 1-chloroacetyl-5- (hept-1-enyl) -6-hydroxy-5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2-one
• Examples 27 and 28 are obtained from the compound obtained in step B of Example 4, by replacing 2-chloroacetyl chloride with 2-chloroacetyl isocyanate, according to the procedure described in step E from example 4.
• EXAMPLE 30 [1-Chloroacetyl-5- (1-chloroacetyl-carbamoyloxy-2-chloro-5-phenylp ⁇ ntyl) -5-methyl-tetrahydro-pyrano [3,2-d] oxazol-2- one] -sp / ro-2'-oxlrane Compound obtained from the compound of Example 9, via treatment with an equivalent of 2-chloroacetyl isocyanate in dichloromethane.
• the organic phase is extracted with dichloromethane. After drying the organic phase over magnesium sulphate, concentration and trituration in ether, the desired compound is obtained, in the form of a white powder.
• SUBSTITUTE SHEET (RULE 26)
• the compounds of Examples 32-2, 32-3 and 32-4 below are obtained by successive cleavages by liquid chromatography (HPLC) on an RP18 column of the compound of Example 17.
• EXAMPLE 32-3 1-Carbamoyl-6-chloroac ⁇ tylcarbamoyl-oxy-5- (hepM-ynyl) -5- methyl-tetrahydropyrano [3,2-d] oxazol-2-one
• EXAMPLE 32-4 1 -Carbamoy l-6-carbamoy loxy-5- (hept-1 -y ny l) -5-méthy l-tétra- hydropyrano [3,2-d] oxazol-2-one
• SUBSTITUTE SHEET (RULE 26
• the compounds of Examples 33 and 34 are obtained according to the procedure described in Example 31, using in step A of Example 1, the appropriate acetylene derivative.
• Step A N- (5-heptyl-5-methyl-2-oxo-perhydropyrano [3,2-d] oxazol-6-yl) acetamide
• Step B N- (1-Chloroacetyl-5-heptyl-5-methyl-2-oxo-perhydropyrano [3,2-d] oxazol-6-yl) acetamide
• step A The compound obtained in step A is treated with 2-chloroacetyl chloride according to the procedure described described in step E of Example 4, to yield the expected product in the form of a white powder Spectral characteristics: NMR 1 H (DMSO), ⁇ (ppm): 8.5 (1H, s); 6.55 (1H, d); 6.15 (1H, d); 5.0 (1H, dd); 4.8 (2H, dd); 2.0 (3H, s); 1.9 (1H, m); 1.55 (1H, m); 1.45 (5H, m); 1.6-1.10 (10H, m); 0.85 (3H, t).
• Step A 5- (hept-1-ynyl) -5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione 6-oxime
• Step B N- (5-heptyl-5-methyl-2-oxo-2,3a, 5,7a-tetrahydro-1 pyrano [3,2-d] oxazol-6-yl) acetamide
• step A 400 mg, 1.4 mol
• an acetic acid (12 ml) / acetic anhydride (40 ml) mixture is stirred in the presence of palladium on carbon (80 mg) under hydrogen atmosphere , at atmospheric pressure and ambient temperature for 14 hours.
• the reaction medium is then filtered through celite, azeotroped with toluene.
• a gummy residue is obtained which is crystallized from a diethyl ether / pentane mixture.
• 240 mg of a beige powder are then obtained which is used as it is subsequently.
• the filtrate mainly consists of 5-heptyl-5-methyl-dihydropyrano [3j2-d] oxazole-2,6-dione 6 (Oacetyloxime) which will be used for the preparation of the compound of Example 42.
• Step C 1-Chloroacetyl-5-hptptyl-5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione 6- (0-acetyloxime)
• step B The compound obtained in step B is treated with 2-chloroacetyl chloride, in the presence of n-butyllrthium under the operating conditions described in step E of Example 4.
• Step A 1- (2-furyl) heptan-1-ol
• reaction medium is then cooled to -78 ° C, and 36.76 ml (262.7 mmol) of heptanal in anhydrous tetrahydrofuran are added dropwise.
• the mixture is again stirred for one hour at -78 ° C.
• the solution is then hydrolyzed with a saturated aqueous solution of sodium chloride and then extracted with pentane.
• the organic phases collected are dried over magnesium sulphate then filtered and concentrated. An orange oil is obtained (38.6 g) corresponding to the expected product, and is used as such subsequently.
• Step B 1-Chloroacetyl-5-hexyl-dihydropyrano [3,2-d] oxazole-2,6-dione
• step A The compound of step A is subjected to the procedures of steps B and C of Example 1 to result in a mixture of two isomers.
• Example 50 Benzyl - [(1-chloroacetyl-6-chloroacetylcarbamoyloxy-5-heptyl-5-methyl-2-oxo-tetrahydropyrano [3,2-d] oxazol-6-yl) methyl] methylsulfonium
• Example 51 2 - [(1-Chloroacetyl-5-heptyl-6-hydroxy-5-methyl-2-oxo-tetrahydropyrano [3,2-d] oxazol-6-yl) methyl] -1, 3-dihydro- benzo [c] thienylium
• Example 53 1-Chloroacetyl-5-hexyl-7-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione Compound obtained by proceeding according to the procedure described in Example 41 from 2-hexyl -6-hydroxy-4-methyl-6H-pyran-3-one (obtained via oxidative rearrangement of 1- [2- (3-methylfuryl)] hexan-1-ol prepared according to Sato et al., J. Org. Chem ., (1989), 54, 2085-2091).
• Example p 54 1-Chloroacetyl-7-methoxy-5-methyl-dihydropyrano [3,2-d] oxazole-2,6-dione
• Example 53 Proceeding as described for Example 53, starting from 6-hydroxy-4-methoxy-2-methyl-6W-pyrane-3-one (obtained via oxidative rearrangement of prepared 3-methoxy-furan-2-yl-methanol according to PA Weeks et al., J. Org. Chem., (1980), 45, 1109).
• Example 63 1-Chloroacetyl-5,7-dim ⁇ thyl-6-methylamino-5- (3-pentyl-oxiran-2-yl) -tetrahydropyrano [3,2-d] oxazol-2-one
• Example 64 1-Chloroacetylcarbamoyloxy-6-diethylamino-5-heptyl-t ⁇ tra-hydro-pyrano [3,2-d] oxazol-2-one
• Three cell lines were used: - 1 murine leukemia, L1210, - 1 human squamous cell carcinoma, A431,
• CEAP pig aorta endothelial cells
• the cells are distributed in microplates and exposed to cytotoxic compounds.
• the cells are then incubated for two days (L1210), 3 days (CEAP) and 4 days (A431).
• the number of viable cells is then quantified by a colorimetric test, the Microculture Tetrazolium Assay (Carmichael J., DeGraff WG, Gazdar AF, Minna JD and Mitchell JR, Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing, Cancer Res., 47, 936-942, (1987)).
• the compounds of the present invention have shown antiproliferative activity on these three cell lines.
• the IC 50 concentration of compound which inhibit the proliferation of the treated cells to 50%
• the cell lines are, depending on the cell lines, from 3 to 10 times lower than those of fumagillin.
• mice were randomly assigned to treated groups (11 mice / group) and to a control group of 40 mice.
• Tumor fragments were implanted on day 0 (subcutaneous implant).
• the test compounds were administered for 12 days (day 1 to day 12) i.p.
• the average tumor weight was determined on day 13 after implantation.
• the percentage of inhibition was calculated according to the formula:
• % Inhibition 100 - mean tumor weight (treatment group) mean tumor weight (control group)
• the compound of Example 31 showed an inhibition of 79% at the dose of 120 mg / kg.

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